Submitted July 16, 2007
Accepted September 17, 2007
Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes
B. N. Yamaja Setty* and Suhita Gayen Betal
Department of Pediatrics, Division of Research Hematology, Marian Anderson Comprehensive Sickle Cell Anemia Care & Research Center, Thomas Jefferson University, Philadelphia, PA, United States
* Corresponding author; email: yamaja.setty{at}jefferson.edu.
Phosphatidylserine (PS)-positive erythrocytes adhere to endothelium and sub-endothelial matrix components. While thrombospondin mediates these interactions, it is unknown whether PS-associated erythrocyte-endothelial adhesion occurs in the absence of plasma ligands. Using ionophore-treated PS-expressing control HbAA erythrocytes, we demonstrate that PS-positive erythrocytes adhered to human lung micro-endothelial cells in the absence of plasma ligands, that this adhesion was enhanced following endothelial activation with IL-1
, TNF-, LPS, hypoxia and heme, and that this adhesive interaction was selective to erythrocyte-PS. We next explored whether micro-endothelial cells express an adhesion receptor that recognizes cell surface expressed PS (PSR) similar to that expressed on activated macrophages. We demonstrate constitutive expression of both PSR mRNA and protein which were up-regulated in a time-dependent manner following endothelial activation. While minimal PSR expression was noted on un-stimulated cells, endothelial activation up-regulated PSR surface expression. In antibody blocking studies, using PS-positive erythrocytes generated either artificially via ionophore treatment of control erythrocytes or from patients with sickle cell disease, we demonstrate that PSR was functional, supporting PS-mediated erythrocyte adhesion to activated endothelium. Our results demonstrate the existence of a novel functional adhesion receptor for PS on the micro-endothelium which is up-regulated by such pathologically relevant agonists as hypoxia, cytokines and heme.
